Angiogenesis has been demonstrated to be a critical component in the growth of many tumors, including lung cancer, breast cancer, and colorectal cancer. Responses to angiogenesis inhibitors alone have been low, though if paired with the combination of other chemotherapy agents, they could be efficacious. Vascular endothelial growth factor (VEGF) is likely the critical component in angiogenesis. Tumor cells produce VEGF, which binds to endothelial cells via one of three VEGF receptors. This induces signal transduction pathways which result in endothelial cell proliferation and hence angiogenesis. The targeting of VEGF has been one of the novel targets being investigated in the search for more efficacious treatments of colorectal cancer.
The treatment of metastatic colorectal (CR) cancer has undergone an evolution in the past few decades. From best supportive care, 5-FU chemotherapy regimens showed efficacy, which has since led to combination regimens including FOLFOX (with oxaliplatin) and FOLFIRI (with irinotecan). Recently, these regimens have been combined with angiogenesis inhibitors. Perhaps the most notable of these is bevacizumab, a 93% humanized monoclonal antibody against VEGF. Bevacizumab has been shown in preclinical and clinical studies to have activity against angiogenesis. It has a long half life of 17-21 days, leading to the requirement of administration only every 2 weeks.
Bevacizumab has recently been reported in a randomized phase II trial. This trial randomized patients to 5-FU plus leucovorin (LV), 5-FU/LV + bevacizumab 5 mg/kg every 2 weeks, or 5-FU/LV + bevacizumab 10 mg/kg every 2 weeks. Both bevacizumab arms showed a longer time to progression and a suggested increased response rate. In addition, the toxicity profile was minimal with only hypertension seen over what is expected with 5-FU alone (24% incidence in the 10 mg arm and 9% in the 5 mg arm).
Bevacizumab has also been combined with IFL chemotherapy (irinotecan with weekly 5-FU/LV) in a three arm phase III trial. Over 800 patients were randomized to IFL + placebo vs. IFL + bevacizumab vs. 5-FU/LV + bevacizumab. In an interim analysis, IFL + bevacizumab was shown to be safe, so the 5-FU/LV arm was subsequently closed. This study, reported at the ASCO 2003 meeting, showed an increased efficacy in all treatment outcomes with the bevacizumab arm. The overall response rate was 35% vs. 45%, duration of response of 7 months vs. 10.4 months, progression free survival of 6.2 months vs. 10.6 months, and overall survival of 15.6 months vs. 20.3. The only increased toxicity was six bowel perforations in the bevacizumab arm, with cause as of yet unknown, as well as hypertension-typical of antiangiogenesis agents.
Bevacizumab has also been demonstrated to be efficacious in combination with oxaliplatin regimens. In a recent trial, there was a comparison of FOLFOX4 vs. FOLFOX4 + bevacizumab vs. bevacizumab alone. In interim analysis, the bevacizumab alone arm was closed due to a trend of decreased survival. Though the full analysis is still pending, toxicity data is available for over 200 patients, with no increased toxicity over FOLFOX4 alone, except for the aforementioned hypertension.
There are other ongoing trials investigating bevacizumab, with combination with capecitabine and other 5-FU and oxaliplatin combinations. Since it appears that bevacizumab has no major increased toxicity, it can be safely investigated in other tumors as well. It has been demonstrated to have an increased efficacy when combined with other standard chemotherapy for colorectal cancer. When compared to IFL, it even demonstrated an increased survival in patients with metastatic disease. For this reason, bevacizumab may be the most promising novel agent today in the fight against colorectal cancer.